Normal skin epidermis is a complex epithelial tissue containing keratinocytes that are proliferating, differentiating, and desquamating. Many common diseases of the skin epidermis, such as psoriasis, squamous cell carcinoma, keratoacanthoma, actinic keratosis, and warts, are characterized by localized abnormal proliferation and growth that is localized. For example, in psoriasis, which is characterized by scaly, red, elevated plaques on the skin, the keratinocytes are known to proliferate much more rapidly than normal. Eczema is a superficial inflammatory process involving primarily the epidermis, marked early by redness, itching, minute papules and vesicles, weeping, oozing, and crusting, and later by scaling, lichenification, and often pigmentation.
Clinical use of available treatments for diseases involving epidermal conditions is often limited by toxicity, either systemic or local. For example, methotrexate, although generally effective for treating epidermal conditions when administered orally, is rarely administered orally for fear of hepatic or bone marrow toxicity. Topical application of methotrexate has minimal or no therapeutic effect. Similarly, although topical application of 5-fluorouracil may be an effective treatment for psoriasis, it is generally considered to be unacceptably irritating. Steroid therapy, though effective, is associated with adverse side effects that are potentially so numerous or serious that prolonged use is discouraged. Photochemotherapy with psoralens and ultraviolet light, or PUVA (psoralens and UV treatment), is generally effective for treatment of epidermal conditions, but it is inconvenient to administer and causes side effects and may even cause photomutagenic and photocarcinogenic reactions.
Many of the existing treatments for wound healing and the relief of pain, itch, and inflammatory conditions, at best, are only moderately or minimally effective. Moreover, their clinical use is often limited by toxicity or undesirable side effects. Considerable research effort has been devoted to ameliorating procedures and compositions for such conditions, but few satisfactory treatments have been developed. Likewise, most therapies available for treating neoplasms and abnormal proliferative cell growth produce undesirable side effects. The compositions of the present invention are therefore directed to pharmaceutical preparations and methods for treating a variety of disorders.
In the past several years, the events that trigger the symptoms associated with hyperproliferative as well as other diseases of the skin are becoming better understood at a cellular level. By understanding the basic processes causing the symptoms of these disorders, treatments can be developed that utilize substances capable of modulating, at a cellular level, the chemical signals that lead to inflammation and cell proliferation.
One important class of chemical signals are the protein kinases, including the enzyme, protein kinase C ("PKC"). PKC is a phospholipid-dependent serine/threonine protein kinase that has a major function in cellular growth control. Protein kinases have been implicated in diseases such as psoriasis, rheumatoid arthritis, cystic fibrosis, asthma, and cancer.
PKC plays a role in the control or modulation of many metabolic and other processes. PKC is a calcium-activated phospholipid-dependent protein kinase that phosphorylates a number of intracellular protein substrates. It relays information in the form of extracellular signals across the membrane to regulate many calcium ion dependent processes.
PKC stimulates the release of phospholipase A2, which causes formation of inflammatory prostaglandins via the arachidonic acid cascade. It has been implicated as a possible intracellular "switch" (signal transducer) involved in inflammation and cell proliferation. For this reason, PKC, as well as other modulators and components of the arachidonic acid cascade, have become targets for therapeutic intervention or modulation in diseases such as psoriasis, rheumatoid arthritis, cystic fibrosis, asthma, cancer, and other inflammatory disorders.
It has been shown that psoriatic plaques have higher concentrations of PKC than normal skin. Thus, excessive PKC activity may be a causative agent of the symptoms of psoriasis.
In addition to being implicated in dermatological diseases, PKC may be involved in other disorders that are effected or regulated in some way by these enzymes. For example, the cardiac regulatory protein troponin is phosphorylated by a calcium-dependent protein kinase. Therefore, PKC modulators may have cardioregulatory activity.
PKC may further be a receptor of tumor promoters and is believed to play a critical role in the carcinogenic process. Phorbol esters and other agents promoting carcinogenesis are believed to exert their carcinogenic effects by activation of PKC, which then activates messenger-independent protein kinases such as MBP (myelin basic protein kinase) and S6P (Kemptide kinase). MBP and S6P are released from phorbol ester-stimulated cells and are believed to be activated by PKC and to be involved in carcinogenesis. They are greatly increased in phorbol ester-stimulated cells. MBP kinase is thought to serve as a central link in cellular signaling pathways in that it is activated by a variety of stimuli, e.g., growth factors, hormones and tumor promoters.
Some investigators believe that the myriad of anticarcinogenic retinoid actions can be explained by their effects as inhibitors of PKC.
There are only a few compounds with potent activity as PKC inhibitors; these include sphingosine, cyclosporine, and certain isoquinoline sulfonamides. Unfortunately, these compounds have toxic or nonspecific side effects prohibiting or limiting their use, or they are not active in vivo. Accordingly, aggressive searches continue for selective PKC modulators for use in the treatment of cancers and other inflammatory diseases, as well as other disorders that are effected by PKC activity.
Other groups of enzymes that appear to exhibit various biochemical activities are the calcium-dependent ATP'ases ("Ca-ATP'ases") and calmodulin-stimulated calcium pump ATP'ases ("calmodulin ATP'ases"). These regulators control the level of calcium ions in cells. Calcium ion concentrations are known to play an important role in both plant and animal cell regulation. Calcium is especially important in controlling constriction of muscle cells and cellular proliferation. It also plays an important role in bone metabolism and motility of spermatozoa.
Inhibitors or modulators of Ca-ATP'ases or calmodulin ATP'ases could provide important therapies for the treatment of biochemical disorders in which they play a role. There are very few known specific inhibitors of Ca-ATP'ases.
There have been claims of medicinal activities of various extracts, particularly peat wax derivatives of peat. However, none of these claims have been substantiated.
Peat is generated by the decomposition of vegetation. Peat is mainly composed of water, and the solid mass usually is only about 10 to 20 percent of the wet weight. The mass contains partially decomposed residues of dead plants combined with decaying microorganisms. Usually, peat accumulates to form a bog. The wetness and accumulated plant litter limit air access to the underlying layers of decaying vegetation. Not far below the wet surface, oxygen is virtually absent, and the decomposition can only proceed anaerobically. The term peat, as used herein, refers generally to microbial degradation products of plants, including peat and peat-derived materials, coal, and coal-derived materials. These materials include humic acids and fulvic acids, which are isolated from peat. Coal-derived material includes leonardite and lignite.
Around the world, peat has been employed for various industrial uses. In some countries such as the former Soviet Union, Finland, and Ireland, peat is primarily a fuel. In certain other countries, e.g., Germany and Finland, peat coke is produced for the metallurgical industry. In the former Soviet Union, a large, diversified peat industry produces peat-derived waxes, sugar for yeast production, and other chemicals. Peat is produced and used exclusively for horticultural purposes in the United States and Canada.
Until now, medical uses of peat derivatives have been very limited. One medicinal product made from peat is Torfot, a Soviet preparation primarily used for ophthalmic diseases. It is made by steam distillation of cotton grass-sedge peat. It contains a variety of volatile compounds including phenols, amines, and saturated carboxylic acids. Moreover, there have been reports of bactericidal and bacteriostatic fractions from reed-sedge peats. However, other investigators have been unable to confirm these activities. Attempts have been made to isolate the active material(s) responsible for these activities, mostly by acid extraction or acid degradation of peats, but no reproducible results have been obtained. Steroids have been isolated from peat; these may account for some of the previous reports of biological activities.
U.S. Pat. No. 4,272,527 claims a topical medicinal preparation containing a therapeutically effective component of an ethanol extract of peat wax resin for cure of skin diseases such as eczema and psoriasis. Crude peat wax, such as described in the latter patent, is produced when the extracting solvent is an aliphatic hydrocarbon. Peat wax is composed of a mixture of esters, acids, alcohols, and hydrocarbons derived from peat.
Unfortunately, however, peat-related compositions of therapeutic interest for the treatment of skin and other disorders have not been isolated to date and processed to an extent providing efficacious results. Therefore, there is a persisting therapeutic need for such biologically active compositions to treat skin and other disorders.